Overproduction of apo B-containing lipoproteins by the liver is responsible for a common form of familial combined hyperlipidemia associated with premature cardiovascular disease. Our proposed mechanistic studies in mice will allow us to identify the factors and processes responsible for regulating the secretion of lipoproteins in normal and hyperlipidemic animals and humans. To achieve this goal, we propose the following Specific Aims: 1) To examine the hypothesis that the relative level of expression of MTP and apo B contribute toward determining the maximal capacity of the liver to assemble and secrete apo B-containing lipoproteins. For these studies we will use inbred C57BL/6 mice which have altered expression of MTP and apo B100. 2) To examine the hypothesis that over-production and secretion of apo B-containing lipoproteins is the basis for familial combined hyperlipidemia. Using a novel mutant mouse clone displaying a genotype and phenotype that closely reflects a human form of familial combined hyperlipidemia, we will determine the molecular basis for this common hyperlipidemic disorder. 3) To define the molecular mechanism responsible for the inactivation of the MTP promoter in L35 cells. L35 cells show a phenotype similar to that of livers from abetalipoproteinemics (i.e. genetic loss of MTP expression and an inability to secrete apo B-containing lipoproteins). We will delineate the mechanism responsible for inactivation of the MTP gene in L35 cells using the promoter constructs that we have shown replicates the transcriptional activity of the endogenous MTP gene. 4) To examine the hypothesis that the relative level of expression of MTP, apo B and lipogenic enzymes displayed by individual liver cells varies dynamically with anatomical localization and changes in physiologic and nutritional state. The knowledge gained from our proposed studies in mice will allow us for the first time to determine the physiologic significance of hypotheses formulated from cultured cell models. New insights gained from these proposed studies should be useful in designing diets and pharmacologic agents that may prevent hyperlipidemia and the formation of atherosclerosis in humans.